Nafisa Wilkinson

St James’s Hospital

Leeds

An Update on Uterine Mesenchymal tumours

Uterine Mesenchymal Tumours

• Smooth Muscle

– Benign

– Unusual SMT mimics of LMS

– STUMP

– Leiomyosarcoma

• Endometrial Stromal Tumours (WHO 2014)

– Stromal nodule

– Low grade (ESS)

– High grade (ESS)

– Undifferentiated Uterine Sarcoma (UUS)

Uterine Mesenchymal Tumours

• Uterine Tumour resembling ovarian sex cord tumours

• Rhabdomyosarcoma

• Perivascular epithelioid cell tumour (PEComa)

• Rare

– Benign: lipoma, haemangioma and lymphangioma

– Malignant: angiosarcoma, liposarcoma, osteosarcoma,

chondrosarcoma

• Myxoid smooth muscle tumours

Benign/ malignant

• Epithelioid smooth muscle tumours

Benign/malignant

ESS : journey through terminology

ESS

• Norris and Taylor 1966

• Endometrial Stromal Sarcoma (morphological classification)

– Cells resemble endometrial stroma in proliferative phase

• 35 cases in study: – range of Mitotic activity and nuclear atypia

Norris and Taylor 1966

• Mitotic activity

– >10MF/10 HPF (50% 5 year survival)

– <10MF/10 HPF (100% 5 year survival but 30% recurred)

• Nuclear atypia

– greater in high grade vs low grade group but overlap

noted.

• This lead to stratification of ESS on MI

– low grade ESS

– high grade ESS

Evans HL 1982

• Cancer 1982

• ESS should be separated from poorly differentiated

endometrial sarcoma (resemblance to endometrial stroma and

arborising vasculature)

• Poorly differentiated ES:

– Larger cells

– Nuclear Hyperchromasia

– Pleomorphism

– Stromal vasculature not prominent

– Frequent necrosis

– Increased mitotic activity but MA was not itself an important

prognosticator

Change KL et al 109 ESS (largest study) 1990

• Primary uterine endometrial stromal neoplasms. A

clinicopathologic study of 117 cases Chang KL, Crabtree GS, Lim-Tan SK, Kempson RL, Hendrickson MR

Am J Surg Pathol. 1990 May;14(5):415-38

• Primary uterine tumour > 0.5 cm in size resemble Prolif Endo

• Serpentine infiltration through myometrium

• Intravascular growth

• Mitotic rate does not predict recurrence in Stage I patients

Silverberg and Kurman (1992)

• Recognised 3 categories: – Low grade ESS

– High Grade ESS

– Undifferentiated Sarcoma

• Made case: importance that tumour must

morphologically resemble stromal cells of

proliferative endometrium

ESS

• WHO classification (2003)

• ESN (endometrial stromal nodules)

• ESS ( “low grade” endometrial stromal sarcoma)

• UES (Undifferentiated endometrial sarcoma)

Prognosis

5 year survival

ESS 85%

UES <50%

Classification

• Greater emphasis placed on morphology of tumour cells

Must resemble stroma of proliferative phase of endometrium

ESS ( WHO 2003)

• Dichotomous system : based on cytology

– ESS (low grade) : tumour cells resemble stroma of proliferative phase

of endometrium

– UES (high grade endometrial sarcoma) no resemblance to

proliferative phase endometrial stroma

– Lacks specific differentiation

– No longer differentiated on mitotic activity but :

• On degree of nuclear atypia

• Tumour necrosis

WHO 2003- Demise of HG-ESS!

• Rationale for demise of HG- ESS:

1. High mitotic activity: Discourage mislabelling of

classic low grade ESS as high grade based on

mitotic activity

2. Misclassification: Recognition that tumours that

had been labelled as HG ESS bore no

morphological resemblance to endometrial stroma

and were undifferentiated pleomorphic uterine

sarcoma

The Grey zone

• Chang et al did recognise a subgroup of ESS that

showed nuclear atypia and increased mitotic activity

that could not be labelled as low grade ESS

• Low grade ESS with some high grade features

• Low grade transformation into high grade ESS

• 2003 Terry Rollason: made a case to retain HGSS

recognising that rare cases encountered where low

grade ESS juxtaposed to HGESS (Haines and Taylor

editors Fox and Wells)

High grade sarcoma

• Kurihara et al 2008

– UES-U (with nuclear uniformity)

– UES-P ( with nuclear pleomorphism)- reflects high grade sarcoma

• Sample size was small 31 cases

– 18 LGESS

– 7 UES-U (uniform)

– 6 UES-P (pleomorphism)

• No apparent clinical differences with regards to clinical

outcome between these two groups (57% vs 60 %)

WHO 2014- Updated grading for EST

• Endometrial stromal

nodule

• Endometrial stromal

sarcoma (low grade)

• Endometrial stromal

sarcoma (high grade)

specific t(10:17)

• Undifferentiated Uterine

Sarcoma

ESN (Stromal nodule)

• Rare neoplasm

• 23-86 years (mean 53 years)

• Definition: WHO

• Benign endometrial stromal tumour that has a well-

circumscribed margin and is composed of cells that resemble

proliferative phase endometrial stroma. Finger-like

projections or immediately adjacent nests of tumour cells

(measuring , 3mm in greatest extent from the main mass)

and , < 3 in number are acceptable. Lymphovascular

invasion excludes the diagnosis.

Endometrial stromal nodule

• Grossly fleshy yellow/tan

• Histology

– Cellular

– Hyalinised

– Cysts (34%)

– Infarct type necrosis (68%)

• Up to 3mm focal irregularity allowed (Tavasoli and Norris 2002)

– < 3 in number

– Lobulated or finger –like projections into adjacent myometrium

– Endometrial Stromal tumour with limited infiltration

– Am J Surg Pathol 2002;26:567 -581

Endometrial stromal nodule

ES neoplasm “endo polyp”

Cellular polypoid lesion no glands as part of lesion

Note base not identified. Diagnosis cannot be made

ESN vs ESS

• Cannot be differentiated on curettage material unless entire

lesion represented in curettage material

• Infiltrative margins/vascular invasion (required)

• Hysterectomy

• EXAMINE PERIPHERY CAREFULLY.

HP endo “polyp”

Need hysterectomy to make a definitive diagnosis

Stromal nodule vs. HC leiomyoma

Stromal nodule Cellular leiomyoma

Fascicular growth

Cellular leiomyoma vs. ESN

Small vessels and cellularity compare with endometrial stromal neoplasm

ESN

Endometrial Stromal Sarcoma

• Main site of origin

– Uterine corpus

• Extra- Uterine Sites

– Ovary

– Peritoneum

Endometrial stromal sarcoma- low grade

Clinical features

• Age usually < 50 years

• Dysfunctional uterine bleeding

• Pelvic or abdominal pain

• Variable sized neoplasm (polypoid / bulky)

• Indolent and protracted course (characterised by

recurrences)

Endometrial stromal sarcoma

Cystic change

Endometrial stromal sarcoma

LG Endometrial Stromal Sarcoma-cells

• Proliferation of small,

round to oval

monomorphic cells

• Scant cytoplasm

• Nuclei have smooth

contours (round to oval

in shape)

ESS

Finger like myometrial permeation

ESS- lymphovascular permeation

Lymphovascular permeation - conspicuous feature

ESS “low grade”

Stroma resembles proliferative phase stroma

Endometrial stromal sarcoma

Cystic change

ESS

Extensive hyalinisation Glandular differentiation

ESS with glandular differentiation

Marked stromal cellularity with familiar small calibre arterioles

ESS with glandular differentiation

• Clement PB, Scully RE. Endometrial stromal sarcomas of the

uterus with extensive endometrioid glandular differentiation:

a report of three cases that caused problems in differential

diagnosis. Int J Gynecol Pathol. 1992 Jul.;11(3):163–173.

• McCluggage WG, Ganesan R, Herrington CS. Endometrial

stromal sarcomas with extensive endometrioid glandular

differentiation: report of a series with emphasis on the

potential for misdiagnosis and discussion of the differential

diagnosis. Histopathology. 2009 Feb. 1;54(3):365–373.

Endometrial stromal sarcoma

“star-burst” pattern of hyalinisation

suggests SM differentiation

Myxoid differentiation

ESS with SM differentiation

Dual cell population

ESS epithelioid differentiation

Distinct epithelioid areas

ESS sex cord like pattern

Endometrial stromal sarcoma

• Variants

– Fibrous/myxoid foci

– Smooth muscle differentiation

– Sex-cord like differentiation

– With endometrial glands

– Epithelioid morphology

– Pseudopapillae formation

– Granular eosinophilic cytoplasm

– Clear cytoplasm

– Rhabdoid features/ skeletal muscle differentiation

Immunohistochemistry of LGESS

• CD10 – strong diffuse positive (usually)

• ER/ PR/ WT1 : typically positive

• SMA - often positive

• Desmin- occasionally positive

• H-caldesmon –negative (+ ve smooth muscle differentiation)

• C-Kit (CD117) – may be positive but no c KIT mutations

• Aromatase

• Androgen receptor –may be positive (sex cord like areas)

• AE1/AE3 – epithelial differentiation

• Inhibin/ calretinin/melan-A and CD99- may be positive

ESS (low grade) Molecular genetics

• t(7;17) -80%

– JAZF1-SUZ12

• t(6;7)- 6%

– PHF1-JAZF1

• t(6;10) -4%

– EPC1-PHF1

• Am J Surg Pathol. 2011

Sep;35(9):1364-72

• Frequency of known

gene rearrangements

in endometrial

stromal tumours

• Chiang S et al.

JAZF1-SUZ12 and JAZF1-PHF1

• Genetic fusions- fusion oncoprotein (transcriptional

dysregulation)

• Oncogenic influences mediated through altered

transcriptional control in endometrial stromal progenitor cells

• Different genotypes

– Exhibit similar clinical behaviour

– Low grade histological features

– Some genetic re-arrangements may be associated with specific

variants (PHF1 rearrangement associated with sex cord

differentiation)

Re-birth of HG ESS (WHO 2014)

• YWHAE-FAM22 (NUTM2)

– Arise from uterus

– Grossly visible mass which is myoinvasive (1-12 cm size)

– May have extra-uterine component

– Tongue-like myoinvasion

– Vascular invasion

– Arborizing stromal capillary network

– Dual cell component (high grade round cell component and low grade

spindle cell component)

– Reminiscent of round blue cell component

HG ESS

Am J Surg Pathol 2012: 36, 641-653

YWHAE-NUTM2 high grade ESS

• UES (WHO 2003) with uniform nuclear features 50% harbour

t(10:17)(q22;p13) translocation

• NUTM2A/B formerly known as FAM22A/B

• Change of nomenclature- sequence homology to NUT

protein (encoded by NUTM1) important in NUT midline

carcinoma

• YWHAE-NUTM2 genetic re-arrangements and

JAZF1/SUZ12 and EPC1/PHF1 genetic re-arrangements

mutually exclusive

Gross appearance uterus

Histology : Variable cellularity

Dual cell population

Rich vascular network comprising thin wall capillaries

Multiple mitoses (>10/10HPF)

Irregular nuclear contours but non-pleomorphic

Myometrial infiltration

Fibromyxoid where tumour permeates myometrium

Cells with round nuclei

Mitoses easily seen, nuclear enlargement 4-6 x size of lymphocyte

YWHAE-NUTM2 HG-ESS

Focal

necrosis

Small round blue cell tumour

Dual cell population

Rich vascular network comprising thin wall capillaries

Vascular permeation

Am J Surg Pathol. 2012 Oct;36(10):1562-70.

Cyclin D 1 diffuse positive

Courtesy Dr Esther Oliva

HG-ESS (YWHAE-NUTM2)

• Immunohistochemistry

• High grade component

– CD10 –ve

– ER –ve

– PR –ve

– Cyclin D1 (>70%) strong, diffuse, nuclear +ve

– C KIT (cytoplasmic strong)

– DOG 1( -ve) in high grade and low grade areas

– Beta-catenin (cytoplasmic) no nuclear positivity

– Negative for:

– EMA, SMA, desmin, caldesmon, HMB-45, Melan A and cytokeratin

FISH t(10;17)(q22;p13)

YWHAE-NUTM2 ESS courtesy Drs Lee and Oliva

Undifferentiated Uterine sarcoma (WHO 2014)

Definition:

• A tumour arising in the endometrium or myometrium, lacking

any resemblance to proliferative –phase endometrial stroma,

with high-grade cytological features and with no specific type

of differentiation

• Rare tumour, patients post menopausal mean age 60 years

• Prognosis: Poor. Patients present with high stage disease

(>60%). Even patients with stage I disease DOD within

2 years

• Adjuvant therapy no therapeutic benefit

Undifferentiated Uterine sarcoma (2014)

• Why replace UES with UUS?

• Not all UES arise from the endometrium WHO 2014

acknowledges this

• More accurate terminology UUS

• No specific lines of mesenchymal differentiation

• Diagnosis of exclusion

Histologic features of Undifferentiated Uterine Sarcoma (UUS)

• Heterogeneous group of sarcomas lacking diagnostic criteria

for:

– ESS (high grade)

– Leiomyosarcoma

– Rhabdomyosarcoma

– Adenosarcoma with sarcomatous overgrowth

– Carcinosarcoma (esp when sarcoma has overgrown carcinoma)

– Undifferentiated or dedifferentiated endometrial carcinoma

– Complex Karyotype (many structural and numerical aberrations)

– High mitotic activity and necrosis

Subset of UUS harbour missense TP53 mutations

DDx leiomyosarcoma

Marked diffuse cytologic atypia

DDx Leiomyosarcoma

Increased cellularity, coagulative necrosis with ghost outlines of cells

DDx Carcinosarcoma

With rhabdomyoblasts-heterologous differentiation

DDx :Adenosarcoma with sarcomatous overgrowth

Adenosarcoma with sarcomatous overgrowth

Sarcomatous overgrowth in adenosarcoma

DDx Undifferentiated carcinoma

DDx Undifferentiated carcinoma

Loss of MMR proteins may be seen

Immunohistochemistry of UUS

• CD10 may be positive NOT- ESS

• Hormone receptors may be positive.

• Focal SMA + (need panel of smooth muscle markers to dx

LMS)

• Consider malignant PEComa

• Focal keratin or EMA consider undifferentiated or de-

differentiated endometrial carcinoma

∂ PEComa

2014 WHO Classification-LGESS

• Low-grade ESS (JAZF1 LGESS and classic ESS without

genetic re-arrangement)-

• Same histology and immunophenotype

– (Cyclin D1<10%) or negative

– CD10 Strong diffuse

– ER strong diffuse

– PR strong diffuse

• Presentation : usually with stage I disease (resectable)

• Prognosis : excellent (small risk of late recurrence -10-20%)

• Rx : anti-oestrogenic therapy useful in disease control

(aromatase inhibitors)

YWHAE-NUTM2 ESS

• Presentation : advanced disease (stage 2-4)

• Treatment : surgery but rapid recurrence recognised (few

months to years)

• Cyclin D1 strong diffuse positive >70% cells

• CD10, ER and PR classically negative in high grade

component). Negative for epithelial markers.

• Anti-oestrogenic therapy (no value)

• Some long term survivors stage 2 or higher have had

survival benefit with adjuvant Rx

– Adjuvant chemotherapy

– Radiation therapy

UUS

• May present at high stage

• Dismal prognosis for patients with stage 2 or greater

• Immunohistochemistry : Variably positive with

immunohistochemical markers used for mesenchymal

tumour diagnosis (no consistency)

• Subset with uniform nuclei +ve for Cyclin D1 focal ER, PR or

CD10 staining may be seen (exclude YWHAE-NUTM2 high

grade ESS)

• Mnx : Non-responsive to conventional chemotherapy or

radiation Rx

Am J Surg Pathol 2012: 36, 641-653

Staging LMS and ESS

Int J Gynecol Obstet 104,179

DDx- rare but consider…..

• Uterus in pelvis

• Pelvis also site of other soft tissue tumours

• Is tumour Uterine in origin?

– Mixed tumours (carcinosarcoma or adenosarcoma) (1block/cm)

– Generous sampling (endometrium)- older people

• Is it arising from outwith the uterus

– Dedifferentiated liposarcoma

– PEComa (rarely from within uterus)

– GIST (gastro-intestinal stromal tumour)

– Peripheral nerve sheath tumour

– Low-grade fibromyxoid sarcoma

High grade sarcoma ( not mixed tumour)

• Once carcinosarcoma and adenosarcoma with

sarcomatous overgrowth excluded:

• Pleomorphic Uterine sarcoma – UUS, leiomyosarcoma, rare heterologous sarcomas (pleomorphic

rhabdomyosarcoma)

• Monomorphic Uterine sarcoma – ESS, leiomyosarcoma or IVL, dedifferentiated or undifferentiated

endometrial carcinoma

– PEComa :(HMB45, Melan A, S100, desmin, SMA, h-caldesmon)-

mTOR inhibitors (recent studies suggested response)

– Ewing’s sarcoma : Cyclin D1 +ve, CD 99, FLI-1

DDX

• Tumour – morphologically low grade ESS

– Growth pattern low grade ESS

– smooth muscle differentiation

• Options?

– Low grade ESS (JAZF1 LGESS or ESS without demonstrable

genetic arrangement) – FISH or RT-PCR for genetic fusions

– Uterine leiomyoma with intravascular leiomyomatosis

– Note unlikely to be HGESS no documentation of associated smooth

muscle differentiation with YWHAE-NUTM2 ESS

De-differentiated ESS

• Biphasic tumour

– Monomorphic low grade component (ovoid cells)

– High grade component (round cells)

• De-differentiated ESS (lacks cyclin D1 positivity)

– Unlike YWHAE- NUTM2 ESS

Diagnosis of Uterine sarcoma

• Need hysterectomy specimen

• Patience

• Very generous sampling

• Small biopsies may not be representative!

Cervical “polyp”

Small round blue cell tumour

Spindle cell component

fibromyxoid stroma